CN108129461A - Benzamido benzo [d] azepine * bases quinazoline compounds and preparation and application - Google Patents
Benzamido benzo [d] azepine * bases quinazoline compounds and preparation and application Download PDFInfo
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Abstract
The invention discloses a kind of benzamido benzo [d] azepinesBase quinazoline compounds and preparation and application.Benzamido benzo [d] azepine provided by the inventionBase quinazoline compounds are respectively provided with significant inhibitory activity to Breast cancer lines MCF 7, human lung carcinoma cell line A 549, are expected to be applied to prepare prevention or treatment human breast carcinoma, the drug of human lung cancer.The present invention provides benzamido benzo [d] azepines
Description
(1) technical field
The present invention relates to a kind of quinazoline compounds and its application, more particularly to a kind of benzamido benzo [d] nitrogen
It is miscellaneousBase quinazoline compounds and preparation method thereof and the compound are in the drug for preparing prevention or treatment tumor disease
In application.
(2) background technology
Quinazoline compounds have many preferable bioactivity, have a wide range of applications in field of medicaments, and especially one
The quinazoline derivative of a little special constructions has apparent antiviral activity, antibacterial activity, antitumor activity etc., quinazoline ditosylate salt
Compound has had listed some kinds as antitumor drug.Such as the Gefitinib for being used to treat lung cancer of listing
(Gefitinib) and Tarceva (Erlotinib) and for treating the Lapatinib of breast cancer (Lapatinib), they
Belong to quinazoline compounds.Also common document report (refers to Y.- for novel quinazoline compounds and its bioactivity
Y.Ke,H.-Y.Shiao,Y.C.Hsu,C.-Y.Chu,W.-C.Wang,Y.-C.Lee,W.-H.Lin,C.-H.Chen,
J.T.A.Hsu,C.-W.Chang,C.-W.Lin,T.-K.Yeh,Y.-S.Chao,M.S.Coumar,H.-P.Hsieh,
ChemMedChem 2013,8,136-148;A.Garofalo,A.Farce,S.Ravez,A.Lemoine,P.Six,
P.Chavatte,L.Goossens,P.Depreux,J.Med.Chem.2012,55,1189-1204).Certainly majority quinazoline
Class compound does not simultaneously have antitumor activity.
(3) invention content
The purpose of the present invention is to provide a kind of novel quinazoline quinoline class compound-benzamidos with active anticancer
Benzo [d] azepineBase quinazoline compounds and its preparation method and application, such compound is under doses to people's lung
Cancer cell line A-549 or MCF-7 cell strainHJ2mm have significant inhibiting rate;And such compounds process for production thereof is easy,
Easily operated, raw material is easy to get, and production cost is relatively low, suitable for industrial applications.
For achieving the above object, the present invention adopts the following technical scheme that:
In a first aspect, the present invention provides benzamido benzo [d] azepines shown in a kind of formula (I)Base quinazoline ditosylate salt
Compound:
Second aspect, the present invention provide benzamido benzo [d] azepine shown in a kind of formula (I)Base quinazoline ditosylate salt
The preparation method of object is closed, the method is:(1) compound shown in formula (II) with compound shown in formula (III) is mixed, had
In solvent A, under the action of basic catalyst B, 25~120 DEG C reacted (TLC tracking and monitorings, solvent be acetic acid second
Ester/petroleum ether=1:3 (v/v), preferably 40~100 DEG C 0.5~12h of reaction), after the reaction was complete, reaction solution is isolated and purified, is made
Obtain compound shown in formula (IV);The organic solvent A is selected from one of following:Chloroform, toluene, methanol, ethyl alcohol, propyl alcohol, isopropanol,
Acetonitrile or N,N-dimethylformamide;The basic catalyst B is selected from one of following:Pyridine, diethylamine, triethylamine, quinoline,
N, N- dimethylaniline, 4-dimethylaminopyridine, 4- pyrollidinopyridines or sodium carbonate (preferably pyridine, diethylamine, triethylamine, N,
N- dimethylanilines or 4-dimethylaminopyridine);
(2) formula (IV) compound represented under reducing agent E effects, has been reacted in organic solvent D at 25~100 DEG C
(TLC tracking and monitorings, solvent are ethyl acetate/petroleum ether=1 entirely:1 (v/v), preferably 40~80 DEG C 0.5~12h of reaction), instead
Liquid is answered to filter, formula (V) compound represented is made in the concentrate drying (preferably 25 DEG C vacuum drying) after filtrate decompression concentration;
The organic solvent D is one of following:Chloroform, toluene, methanol, ethyl alcohol, propyl alcohol, isopropanol, acetonitrile or N, N- dimethyl formyl
Amine;The reducing agent E is one of following:Iron powder/concentrated hydrochloric acid, iron powder/acetic acid, palladium carbon/ammonium formate or palladium carbon/hydrazine hydrate;It is described
Iron powder/concentrated hydrochloric acid refers to that the mixing of iron powder and concentrated hydrochloric acid arbitrary proportion, iron powder/acetic acid refer to the mixed of iron powder and acetic acid arbitrary proportion
It closes, the palladium carbon/ammonium formate refers to the mixing of palladium carbon and ammonium formate arbitrary proportion, and the palladium carbon/hydrazine hydrate is palladium carbon and hydration
The mixture of hydrazine arbitrary proportion;
(3) compound shown in formula (V) is mixed with chlorobenzoyl chloride or benzoyl oxide, under basic catalyst F effects, in
In organic solvent G, -10~50 DEG C the reaction was complete, and (TLC tracking and monitorings, solvent are ethyl acetate/petroleum ether=1:1 (v/v),
It is preferred that -10~50 DEG C of 3~12h of reaction), reaction solution is post-treated, and formula (I) compound represented is made;The base catalysis
Agent F is one of following:Pyridine, diethylamine, triethylamine, quinoline, N, N- dimethylanilines, 4-dimethylaminopyridine, 4- pyrrolidinyls
Pyridine or sodium carbonate;The organic solvent G is one of following:Tetrahydrofuran, dichloromethane, chloroform, ethyl acetate, ether, second
Nitrile, toluene or benzene;
Further, in step (1), compound shown in compound shown in the formula (III) and formula (II), basic catalyst B
The ratio between the amount of substance of feeding intake is 1.0 ﹕, 0.8~1.2 ﹕ 1.0~8.0.
Further, in step (1), the dosage of the organic solvent A is calculated as 10 with the quality of compound shown in formula (III)~
50mL/g。
Further, the method that reaction solution isolates and purifies described in step (1) of the present invention is:After the reaction was complete, by reaction solution
Solvent is evaporated off, concentrate is taken to be dissolved with organic solvent C, obtain lysate, then into lysate add in concentrate 1.0~
After mixing, solvent is evaporated off in the column chromatography silica gel of 2.0 times of weight, dry, the mixture of concentrate and silica gel is obtained, by mixture
Column is filled, then using volume ratio as 1:0.1~10 petroleum ether is eluant, eluent with ethyl acetate mixture, is collected containing target components
Efflux (preferably with ethyl acetate/petroleum ether=1:3 (v/v) are solvent tracing detection, collect target components, preferably receive
Collect the component that Rf values are 0.5), it is concentrated under reduced pressure, dry (preferably 50 DEG C of dryings) obtain formula (IV) compound represented;It is described to have
Solvent C is one of following:Ethyl alcohol, chloroform, tetrahydrofuran or ethyl acetate.The organic solvent C dosages are residual can dissolve
Stay object.
Further, in step (2), when the reducing agent E is iron powder/concentrated hydrochloric acid or iron powder/acetic acid, formula (IV) institute
The mass ratio that feeds intake of iron powder, concentrated hydrochloric acid or acetic acid in the compound and reducing agent E shown is 1.0 ﹕, 1.0~3.0 ﹕ 0.2~1.0.
In the present invention, concentrated hydrochloric acid mass concentration is 36%~38%, and acetic acid uses glacial acetic acid.
Further, in step (2), when the reducing agent E is palladium carbon/ammonium formate or palladium carbon/hydrazine hydrate, formula (IV) institute
The compound shown in reducing agent E palladium carbon, ammonium formate or hydrazine hydrate feed intake mass ratio for 1.0 ﹕, 0.1~0.5 ﹕ 1.0~
3.0.The mass loading amount of palladium is 2~10%, preferably 5% in the palladium carbon being applicable in the present invention, hydrazine hydrate mass concentration for 40~
80%, preferably 80%.
Further, in step (2), the dosage of the organic solvent D is calculated as 10 with the quality of formula (IV) compound represented
~50mL/g.
Further, in step (3), compound shown in the formula (V) and chlorobenzoyl chloride or benzoyl oxide, base catalysis
The ratio between amount for the substance that feeds intake of agent F is 1 ﹕, 1.0~8.0 ﹕ 1.0~3.0.
Further, in step (3), the dosage of the organic solvent G is calculated as 11 with the quality of compound shown in formula (V)~
100mL/g。
Further, step (3) carries out as follows:Under the conditions of -10~10 DEG C, toward compound shown in formula (V) and
Chlorobenzoyl chloride is added dropwise in the organic solvent G solution of basic catalyst F or into compound and basic catalyst F shown in formula (V)
Or the organic solvent G solution of benzoyl oxide, drop finish, -10~50 DEG C are reacted 3~12 hours, and gained reaction solution is post-treated to be obtained
Compound shown in formula (I);Dissolving the organic solvent volume dosage of chlorobenzoyl chloride or benzoyl oxide does not influence the present invention, described to have
Total dosage of solvent G is calculated as 11~100mL/g with the quality of compound shown in formula (V).Total dosage of organic solvent G refers to
Dissolve the organic solvent G of compound shown in basic catalyst F and formula (V) and dissolving chlorobenzoyl chloride or benzoyl oxide organic solvent G
Total volume.
Further, the method for step (3) the of the present invention reaction solution post processing is:After the reaction was complete, reaction solution is filtered,
Filtrate steaming removal solvent takes concentrate to be dissolved with organic solvent H, obtains lysate, concentrate is then added in into lysate
After mixing, solvent is evaporated off in the column chromatography silica gel of 1.0~2.0 times of weight, dry, obtains the mixture of concentrate and silica gel, will be mixed
Object dress column is closed, then using volume ratio as 1:0.1~10 petroleum ether is eluant, eluent with ethyl acetate mixture, is collected containing target
The efflux of component is (preferably with ethyl acetate/petroleum ether=1:1 (v/v) is solvent tracing detection, collects target components, excellent
The component that Rf values are 0.5 is collected in choosing), it is concentrated under reduced pressure, dry (preferably 50 DEG C of dryings) obtain formula (I) compound represented;It is described
Organic solvent H is one of following:Ethyl alcohol, chloroform, tetrahydrofuran or ethyl acetate.The organic solvent H dosages are can dissolve
Residue.
Organic solvent A of the present invention, C, D, G and H are organic solvent, organic used in different step for the ease of distinguishing
Solvent is different and names, and letter itself does not have meaning;The catalyst B, reducing agent E and catalyst F are catalyst, in order to just
It is named in differentiation different step used catalyst difference, letter itself does not have meaning.
The third aspect, the invention further relates to benzamido benzo [d] azepines shown in formula (I)Base quinazoline compounds
Application in prevention or tumor is prepared, particularly useful for making answering in prevention or treatment human breast carcinoma drug
With.
Preferably, the drug is with the drug for inhibiting MCF-7 cell strainHJ2mm activity.Provided by the inventionization
Close object has preferable inhibition to MCF-7 cell strainHJ2mm.
Benzamido benzo [d] azepine shown in formula (I) of the present inventionBase quinazoline compounds are also to human lung cancer
Cell strain A-549 has significant inhibiting effect, can be applied to the drug for preparing prevention or treatment human lung cancer.
The beneficial effects are mainly as follows:(1) provide it is a kind of it is novel, have well it is antitumor (especially
Human breast carcinoma or human lung cancer) activity benzamido benzo [d] azepineBase quinazoline compounds (I), are expected to apply
Prevent in preparing or treat in the drug of tumor disease, especially human breast carcinoma or human lung cancer;(2) benzoyl provided by the invention
Amino benzo [d] azepineThe preparation method of base quinazoline compounds (I), simple easily operated, raw material is easy to get, and is produced into
This is relatively low, suitable for practicality.
(4) specific embodiment
The present invention be further described in conjunction with specific embodiments, following embodiment illustrate the present invention rather than
It limit the invention in any way.
Compound (II) prepare reference literature (Weinstock, J.et al.J.Med.Chem., 1986,29 (11),
Method 2315-2325) is prepared.The chloro- 6- nitro-quinazolines (III) of 4- prepare reference literature (Fernandes, C.et
Al.Bioorg.Med.Chem., 2007,15 (12), 3974-3980) method be prepared.
Palladium carbon (Pd/C) model D5H5A that the embodiment of the present invention uses, is purchased from Shaanxi Ruike New Materials Co., Ltd..
Embodiment 1:Nitro benzo [d] azepineThe preparation of base quinazoline (IV)
Successively by the chloro- 6- nitro-quinazolines (III) of 1.20 grams of (5.73mmol) 4- and 2.39 grams of (6.87mmol) compounds
(II), 3.62 grams of (45.76mmol) pyridines, 12 milliliters of chloroforms are added in 50 milliliters of reaction bulb, are heated to 40 DEG C, TLC tracking
(solvent is ethyl acetate/petroleum ether=1 for detection:3 (v/v)), it is stirred to react 10 hours, closes reaction, reaction solution is evaporated off molten
Agent adds in 10 milliliters of ethyl acetate in obtained concentrate and is dissolved, obtains lysate, 3.0 grams of columns are added in into lysate
Chromatographic silica gel (300~400 mesh column chromatography silica gel) after mixing, is evaporated off solvent, obtains the mixture of dry concentrate and silica gel,
Mixture is filled into column, then using volume ratio as 1:10 petrol ether/ethyl acetate mixed solution is eluant, eluent, is eluted, TLC tracking
(solvent is ethyl acetate/petroleum ether=1 for detection:3 (v/v)), it is collected according to TLC detections containing formula (IV) compound represented
Eluent (Rf values are 0.5), collection liquid concentration, 50 DEG C are dried to obtain the faint yellow solid product shown in formula (IV), yield
85.1%, 164~166 DEG C of fusing point.1H NMR(500MHz,CDCl3)δ:3.32-3.38 (m, 1H), 3.63 (dt, J=3.4,
15.5Hz, 1H), 3.75 (s, 3H), 3.82 (s, 6H), 3.91 (dd, J=8.1,14.3Hz, 1H), 4.03 (td, J=4.1,
11.7Hz, 1H), 4.15 (d, J=11.5Hz, 1H), 4.72 (dd, J=8.3,14.2Hz, 1H), 5.14 (t, J=8.9Hz,
1H), 6.60 (s, 1H), 6.90 (d, J=8.7Hz, 2H), 7.08 (d, J=8.6Hz, 2H), 7.93 (d, J=9.1Hz, 1H),
8.48 (dd, J=2.4,9.2Hz, 1H), 8.71 (s, 1H), 8.96 (d, J=2.4Hz, 1H).IR(KBr,cm-1)ν:2917,
2848,1616,1580,1510,1463,1355,1327,1249,1038,847。
Embodiment 2:Nitro benzo [d] azepineThe preparation of base quinazoline (IV)
Successively by the chloro- 6- nitro-quinazolines (III) of 1.20 grams of (5.73mmol) 4- and 1.59 grams of (4.57mmol) compounds
(II), 1.67 grams of (22.83mmol) diethylamine, 60 milliliters of toluene are added in 100 milliliters of three-necked flask, are heated to 100 DEG C,
(solvent is ethyl acetate/petroleum ether=1 to TLC tracing detections:3 (v/v)), it is stirred to react 2 hours, closes reaction, reaction solution
Solvent is evaporated off, 20 milliliters of ethyl alcohol are added in obtained concentrate and are dissolved, obtain lysate, 2.5 grams are added in into lysate
Column chromatography silica gel (300~400 mesh column chromatography silica gel) after mixing, is evaporated off solvent, obtains the mixing of dry concentrate and silica gel
Mixture is filled column, then using volume ratio as 1 by object:5 petrol ether/ethyl acetate mixed solution be eluant, eluent, elution, TLC with
(solvent is ethyl acetate/petroleum ether=1 for track detection:3 (v/v)), it is collected according to TLC detections containing formula (IV) compound represented
Eluent (Rf values be 0.5), collection liquid concentration, 50 DEG C are dried to obtain the faint yellow solid product shown in formula (IV), yield
72.6%, 164~166 DEG C of fusing point.1H NMR and IR is the same as embodiment 1.
Embodiment 3:Nitro benzo [d] azepineThe preparation of base quinazoline (IV)
Successively by the chloro- 6- nitro-quinazolines (III) of 1.20 grams of (5.73mmol) 4- and 1.99 grams of (5.72mmol) compounds
(II), 0.58 gram of (5.73mmol) triethylamine, 60 milliliters of ethyl alcohol are added in 100 milliliters of three-necked flask, are heated to 60 DEG C, TLC
(solvent is ethyl acetate/petroleum ether=1 to tracing detection:3 (v/v)), it is stirred to react 8 hours, closes reaction, reaction solution is evaporated off
Solvent adds in 20 milliliters of chloroforms in obtained concentrate and is dissolved, obtains lysate, 2.5 grams of column layers are added in into lysate
Silica gel (300~400 mesh column chromatography silica gel) is analysed, after mixing, solvent is evaporated off, obtains the mixture of dry concentrate and silica gel, it will
Mixture fills column, then using volume ratio as 10:1 petrol ether/ethyl acetate mixed solution is eluant, eluent, and elution, TLC, which is tracked, to be examined
(solvent is ethyl acetate/petroleum ether=1 for survey:3 (v/v)), it is detected according to TLC and collects washing for (IV) compound represented Han formula
De- liquid (Rf values are 0.5), collection liquid concentration, 50 DEG C are dried to obtain the faint yellow solid product shown in formula (IV), yield 77.2%,
164~166 DEG C of fusing point.1H NMR and IR is the same as embodiment 1.
Embodiment 4:Nitro benzo [d] azepineThe preparation of base quinazoline (IV)
Successively by the chloro- 6- nitro-quinazolines (III) of 1.20 grams of (5.73mmol) 4- and 2.20 grams of (6.32mmol) compounds
(II), 1.40 grams of (11.46mmol) 4-dimethylaminopyridine, 60 milliliters of isopropanols are added in 100 milliliters of three-necked flask, room temperature
25 DEG C of stirrings, (solvent is ethyl acetate/petroleum ether=1 to TLC tracing detections:3 (v/v)), it reacts 12 hours, closes reaction,
Solvent is evaporated off in reaction solution, and 20 milliliters of tetrahydrofurans are added in obtained concentrate and are dissolved, lysate are obtained, into lysate
4.0 grams of column chromatography silica gels (300~400 mesh column chromatography silica gel) are added in, after mixing, solvent is evaporated off, obtains dry concentrate and silicon
Mixture is filled column, then using volume ratio as 5 by the mixture of glue:1 petrol ether/ethyl acetate mixed solution is eluant, eluent, is washed
De-, (solvent is ethyl acetate/petroleum ether=1 to TLC tracing detections:3 (v/v)), it is collected according to TLC detections containing shown in formula (IV)
Compound eluent (Rf values be 0.5), collection liquid concentration, 50 DEG C of faint yellow solids productions being dried to obtain shown in formula (IV)
Object, yield 80.2%, 164~166 DEG C of fusing point.1H NMR and IR is the same as embodiment 1.
Embodiment 5:Nitro benzo [d] azepineThe preparation of base quinazoline (IV)
Successively by the chloro- 6- nitro-quinazolines (III) of 1.20 grams of (5.73mmol) 4- and 1.79 grams of (5.15mmol) compounds
(II), 1.04 grams of (8.58mmol) N, N- dimethylanilines, 12 milliliters of n,N-Dimethylformamide are added in 50 milliliters of reaction bulb,
120 DEG C are heated to, (solvent is ethyl acetate/petroleum ether=1 to TLC tracing detections:3 (v/v)), it is stirred to react 0.5 hour, closes
Reaction is closed, solvent is evaporated off in reaction solution, and 20 milliliters of tetrahydrofurans are added in obtained concentrate and are dissolved, obtain lysate, to
5.0 grams of column chromatography silica gels (300~400 mesh column chromatography silica gel) are added in lysate, after mixing, solvent is evaporated off, are obtained dry dense
Mixture is filled column, then using volume ratio as 1 by the mixture of contracting object and silica gel:1 petrol ether/ethyl acetate mixed solution is
Eluant, eluent, elution, (solvent is ethyl acetate/petroleum ether=1 to TLC tracing detections:3 (v/v)), it is collected and contained according to TLC detections
The eluent (Rf values be 0.5) of formula (IV) compound represented, collection liquid concentration, 50 DEG C be dried to obtain it is yellowish shown in formula (IV)
Color solid product, yield 89.6%, 164~166 DEG C of fusing point.1HNMR and IR is the same as embodiment 1.
Embodiment 6:Nitro benzo [d] azepineThe preparation of base quinazoline (IV)
Successively by the chloro- 6- nitro-quinazolines (III) of 1.20 grams of (5.73mmol) 4- and 2.39 grams of (6.87mmol) compounds
(II), 3.62 grams of (45.76mmol) pyridines, 20 milliliters of propyl alcohol are added in 50 milliliters of reaction bulb, are heated to 40 DEG C, TLC tracking
(solvent is ethyl acetate/petroleum ether=1 for detection:3 (v/v)), it is stirred to react 10 hours, closes reaction, reaction solution is evaporated off molten
Agent adds in 20 milliliters of ethyl acetate in obtained concentrate and is dissolved, obtains lysate, 3.5 grams of columns are added in into lysate
Chromatographic silica gel (300~400 mesh column chromatography silica gel) after mixing, is evaporated off solvent, obtains the mixture of dry concentrate and silica gel,
Mixture is filled into column, then using volume ratio as 1:1 petrol ether/ethyl acetate mixed solution is eluant, eluent, is eluted, TLC tracking
(solvent is ethyl acetate/petroleum ether=1 for detection:3 (v/v)), it is collected according to TLC detections containing formula (IV) compound represented
Eluent (Rf values are 0.5), collection liquid concentration, 50 DEG C are dried to obtain the faint yellow solid product shown in formula (IV), yield
78.3%, 164~166 DEG C of fusing point.1H NMR and IR is the same as embodiment 1.
Embodiment 7:Amino benzo [d] azepineThe preparation of base quinazoline (V)
0.40 gram of (0.77mmol) nitro benzo [d] azepine successively prepared by 1 method of embodimentBase quinazoline (IV),
0.40 gram of (6.34mmol) ammonium formate, 0.04 gram of 5%Pd/C, 4.0 milliliters of chloroforms are added in reaction bulb, 25 DEG C of stirrings of room temperature,
(solvent is ethyl acetate/petroleum ether=1 to TLC tracing detections:1 (v/v)), it reacts 12 hours, filtering, filtrate concentration, 25 DEG C
Vacuum drying obtains faint yellow solid product amino benzo [d] azepineBase quinazoline (V), yield 98.2%, fusing point 122~
126℃。1H NMR(500MHz,CDCl3)δ:3.40-3.48(m,2H),3.71(s,3H),3.82(s,3H),3.83(s,3H),
3.87-3.98 (m, 5H), 4.45 (dd, J=6.3,13.8Hz, 1H), 4.95 (dd, J=6.5,9.2Hz, 1H), 6.47 (s,
1H), 6.90 (d, J=8.7Hz, 2H), 6.95 (d, J=2.5Hz, 1H), 7.11 (d, J=8.6Hz, 2H), 7.15 (dd, J=
8.9,2.5Hz, 1H), 7.69 (d, J=8.9Hz, 1H), 8.50 (s, 1H).IR(KBr,cm-1)ν:3368,3215,2932,
2825,1628,1566,1512,1487,1353,1248,1036,834。
Embodiment 8:Amino benzo [d] azepineThe preparation of base quinazoline (V)
0.40 gram of (0.77mmol) nitro benzo [d] azepine successively prepared by 2 method of embodimentBase quinazoline (IV),
1.20 grams of (19.18mmol) 80wt% hydrazine hydrates, 0.20 gram of 5%Pd/C, 20.0 milliliters of toluene are added to 50 milliliters of reaction bulb
In, 100 DEG C are heated to, (solvent is ethyl acetate/petroleum ether=1 to TLC tracing detections:1 (v/v)), it is small to be stirred to react 0.5
When, cold filtration, filtrate concentrates, and 25 DEG C of vacuum drying obtain faint yellow solid product amino benzo [d] azepineBase quinazoline
(V), yield 100.0%, 122~126 DEG C of fusing point.1H NMR and IR is the same as embodiment 7.
Embodiment 9:Amino benzo [d] azepineThe preparation of base quinazoline (V)
0.40 gram of (0.77mmol) nitro benzo [d] azepine successively prepared by 3 method of embodimentBase quinazoline (IV),
0.08 gram of concentrated hydrochloric acid (mass concentration 36~38%), 0.40 gram of iron powder, 20.0 ml methanols are added in 50 milliliters of reaction bulb,
40 DEG C are heated to, (solvent is ethyl acetate/petroleum ether=1 to TLC tracing detections:1 (v/v)), it is stirred to react 8 hours, cools down
Filtering, filtrate concentration, 25 DEG C of vacuum drying obtain faint yellow solid product amino benzo [d] azepineBase quinazoline (V) is received
Rate 94.1%, 122~126 DEG C of fusing point.1HNMR and IR is the same as embodiment 7.
Embodiment 10:Amino benzo [d] azepineThe preparation of base quinazoline (V)
0.40 gram of (0.77mmol) nitro benzo [d] azepine successively prepared by 4 method of embodimentBase quinazoline (IV),
0.40 gram of acetic acid, 1.20 grams of iron powders, 20.0 milliliters of isopropanols are added in 50 milliliters of reaction bulb, are heated to 80 DEG C, TLC tracking
(solvent is ethyl acetate/petroleum ether=1 for detection:1 (v/v)), it is stirred to react 3 hours, cold filtration, filtrate concentration, 25 DEG C
Vacuum drying obtains faint yellow solid product amino benzo [d] azepineBase quinazoline (V), yield 97.5%, fusing point 122~
126℃。1H NMR and IR is the same as embodiment 7.
Embodiment 11:Benzamido benzo [d] azepineThe preparation of base quinazoline (I)
0.27 gram of (0.55mmol) amino benzo [d] azepine successively prepared by 7 method of embodimentBase quinazoline (V),
0.13 gram of (1.64mmol) pyridine, 3 milliliters of tetrahydrofurans are added in reaction bulb, and 0.618 gram is added dropwise under -10 DEG C of stirring conditions
(4.40mmol) chlorobenzoyl chloride, drop finish, and (solvent is ethyl acetate/petroleum ether=1 to TLC tracing detections:1), under the conditions of -10 DEG C
Reaction 12 hours, filtering, filtrate steaming removal solvent, concentrate add in 10 milliliters of ethyl acetate and are dissolved, and obtain lysate, Xiang Rong
It solves and 0.60 gram of column chromatography silica gel (300~400 mesh column chromatography silica gel) is added in liquid, after mixing, solvent is evaporated off, obtains dry concentration
Mixture is filled column, then using volume ratio as 1 by the mixture of object and silica gel:10 petrol ether/ethyl acetate mixed solution is washes
De- agent, elution, (solvent is ethyl acetate/petroleum ether=1 to TLC tracing detections:1 (v/v)), it is collected according to TLC detections containing formula
(I) eluent (Rf values are 0.5) of compound represented, collection liquid concentration, 50 DEG C are dried to obtain the benzene carbon amide shown in formula (I)
Base benzo [d] azepineBase quinazoline pale solid, yield 55.4%, 152~153 DEG C of fusing point.1H NMR(500MHz,
CDCl3)1H NMR(500MHz,CDCl3)δ:3.28-3.34 (m, 1H), 3.56 (dt, J=3.6,15.4Hz, 1H), 3.74 (s,
3H), 3.81-3.84 (m, 7H), 4.00-4.10 (m, 2H), 4.68 (dd, J=8.3,14.4Hz, 1H), 5.31 (t, J=
8.7Hz, 1H), 6.70 (s, 1H), 6.88 (d, J=8.7Hz, 2H), 7.10 (d, J=8.7Hz, 2H), 7.54-7.63 (m, 4H),
7.85 (d, J=8.9Hz, 1H), 7.95 (d, J=7.3Hz, 2H), 8.13 (s, 1H), 8.60 (s, 1H), 8.86 (s, 1H).
HRMS-ESI m/z:595.2107[M+H]+。IR(KBr,cm-1)ν:2996,2935,2825,1668,1599,1550,1523,
1488,1463,1349,1249,1108,1037,837。
Embodiment 12:Benzamido benzo [d] azepineThe preparation of base quinazoline (I)
0.27 gram of (0.55mmol) amino benzo [d] azepine successively prepared by 8 method of embodimentBase quinazoline (V),
0.04 gram of (0.55mmol) diethylamine, 10.0 milliliters of chloroforms are added in 50 milliliters of reaction bulb, are added dropwise under 10 DEG C of stirring conditions
0.077 gram of (0.55mmol) chlorobenzoyl chloride and 5.0 milliliters of chloroform mixed solutions, drop finish, and (solvent is acetic acid to TLC tracing detections
Ethyl ester/petroleum ether=1:1 (v/v)), it reacts 8 hours under the conditions of 10 DEG C, filters, filtrate steaming removal solvent, concentrate adds in 20 milliliters
Ethyl alcohol is dissolved, and obtains lysate, and 0.26 gram of column chromatography silica gel (300~400 mesh column chromatography silica gel) is added in into lysate,
After mixing, solvent is evaporated off, obtains the mixture of dry concentrate and silica gel, mixture is filled into column, then using volume ratio as 1:5
Petrol ether/ethyl acetate mixed solution is eluant, eluent, and elution, (solvent is ethyl acetate/petroleum ether=1 to TLC tracing detections:1
(v/v)) eluent (Rf values are 0.5) containing formula (I) compound represented, is collected according to TLC detections, collection liquid concentrates, 50 DEG C
It is dried to obtain benzamido benzo [d] azepine shown in formula (I)Base quinazoline pale solid, yield 53.8%, fusing point
152~153 DEG C.1H NMR and IR is the same as embodiment 11.
Embodiment 13:Benzamido benzo [d] azepineThe preparation of base quinazoline (I)
0.27 gram of (0.55mmol) amino benzo [d] azepine successively prepared by 9 method of embodimentBase quinazoline (V),
0.111 gram of (1.10mmol) triethylamine, 10.0 milliliters of ethyl acetate are added in 50 milliliters of reaction bulb, under 0 DEG C of stirring condition
0.155 gram of (1.10mmol) chlorobenzoyl chloride and 5.0 milliliters of ethyl acetate solutions are added dropwise, drop finishes, and (solvent is TLC tracing detections
Ethyl acetate/petroleum ether=1:1) it, reacts 6 hours under the conditions of 25 DEG C, filters, filtrate steaming removal solvent, concentrate adds in 20 milliliters
Chloroform is dissolved, and obtains lysate, and 0.30 gram of column chromatography silica gel (300~400 mesh column chromatography silica gel) is added in into lysate,
After mixing, solvent is evaporated off, obtains the mixture of dry concentrate and silica gel, mixture is filled into column, then using volume ratio as 10:1
Petrol ether/ethyl acetate mixed solution for eluant, eluent, elution, TLC tracing detections (solvent for ethyl acetate/petroleum ether=
1:1 (v/v)), the eluent (Rf values are 0.5) containing formula (I) compound represented is collected according to TLC detections, collection liquid concentrates, and 50
DEG C it is dried to obtain benzamido benzo [d] azepine shown in formula (I)Base quinazoline pale solid, yield 64.8% melt
152~153 DEG C of point.1H NMR and IR is the same as embodiment 11.
Embodiment 14:Benzamido benzo [d] azepineThe preparation of base quinazoline (I)
0.27 gram of (0.55mmol) amino benzo [d] azepine successively prepared by 10 method of embodimentBase quinazoline
(V), 0.067 gram of (0.55mmol) 4-dimethylaminopyridine, 20.0 milliliters of toluene are added in 50 milliliters of reaction bulb, and 5 DEG C are stirred
The solution of 0.498 gram of (2.20mmol) benzoyl oxide and 7.0 milliliters of toluene is added dropwise under the conditions of mixing, drop finishes, and is heated to 50 DEG C, TLC
(solvent is ethyl acetate/petroleum ether=1 to tracing detection:1) it, reacts 3 hours, filtering, filtrate steaming removal solvent, concentrate adds in
20 milliliters of tetrahydrofurans are dissolved, and obtain lysate, and 0.40 gram of column chromatography silica gel (300~400 mesh column is added in into lysate
Chromatographic silica gel), after mixing, solvent is evaporated off, obtains the mixture of dry concentrate and silica gel, mixture is filled into column, then with body
Product is than being 5:1 petrol ether/ethyl acetate mixed solution be eluant, eluent, elution, TLC tracing detections (solvent for ethyl acetate/
Petroleum ether=1:1 (v/v)), the eluent (Rf values are 0.5) containing formula (I) compound represented is collected according to TLC detections, is collected
Liquid concentrates, 50 DEG C of benzamido benzo [d] azepines being dried to obtain shown in formula (I)Base quinazoline pale solid, yield
45.2%, 152~153 DEG C of fusing point.1H NMR and IR is the same as embodiment 11.
Embodiment 15:Benzamido benzo [d] azepineThe preparation of base quinazoline (I)
0.27 gram of (0.55mmol) amino benzo [d] azepine successively prepared by 7 method of embodimentBase quinazoline (V),
0.213 gram of (1.65mmol) quinoline, 15.0 milliliters of benzene are added in 50 milliliters of reaction bulb, are added dropwise under -10 DEG C of stirring conditions
The solution of 0.309 gram of (2.20mmol) chlorobenzoyl chloride and 5.0 milliliters of benzene, drop finish, TLC tracing detections (solvent for ethyl acetate/
Petroleum ether=1:1) it, reacts 12 hours under the conditions of -10 DEG C, filters, filtrate steaming removal solvent, concentrate adds in 20 milliliters of tetrahydrofurans
It is dissolved, obtains lysate, 0.40 gram of column chromatography silica gel (300~400 mesh column chromatography silica gel), mixing are added in into lysate
Afterwards, solvent is evaporated off, obtains the mixture of dry concentrate and silica gel, mixture is filled into column, then using volume ratio as 1:1 oil
Ether/ethyl acetate mixture is eluant, eluent, and elution, (solvent is ethyl acetate/petroleum ether=1 to TLC tracing detections:1(v/
V)), the eluent (Rf values are 0.5) containing formula (I) compound represented, collection liquid concentration, 50 DEG C of dryings are collected according to TLC detections
Obtain benzamido benzo [d] azepine shown in formula (I)Base quinazoline pale solid, yield 63.7%, fusing point 152~
153℃。1H NMR and IR is the same as embodiment 11.
Embodiment 16:Benzamido benzo [d] azepineThe preparation of base quinazoline (I)
0.27 gram of (0.55mmol) amino benzo [d] azepine successively prepared by 7 method of embodimentBase quinazoline (V),
0.164 gram of (1.10mmol) 4- pyrollidinopyridine, 15.0 milliliters of dichloromethane are added in 50 milliliters of reaction bulb, and 10 DEG C are stirred
0.155 gram of (1.10mmol) chlorobenzoyl chloride and 5.0 milliliters of dichloromethane solutions are added dropwise under the conditions of mixing, drop finishes, TLC tracing detections
(solvent is ethyl acetate/petroleum ether=1:1) it, reacts 8 hours under the conditions of 10 DEG C, filters, filtrate steaming removal solvent, concentrate adds
Enter 20 milliliters of ethyl alcohol to be dissolved, obtain lysate, 0.50 gram of column chromatography silica gel (300~400 mesh column layer is added in into lysate
Analyse silica gel), after mixing, solvent is evaporated off, obtains the mixture of dry concentrate and silica gel, mixture is filled into column, then with volume
Than being 10:1 petrol ether/ethyl acetate mixed solution be eluant, eluent, elution, TLC tracing detections (solvent for ethyl acetate/
Petroleum ether=1:1 (v/v)), the eluent (Rf values are 0.5) containing formula (I) compound represented is collected according to TLC detections, is collected
Liquid concentrates, 50 DEG C of benzamido benzo [d] azepines being dried to obtain shown in formula (I)Base quinazoline pale solid, yield
66.1%, 152~153 DEG C of fusing point.1H NMR and IR is the same as embodiment 11.
Embodiment 17:Active anticancer testing in vitro
(1) compound (I) obtained in embodiment is subjected to human lung cancer and human breast carcinoma biological activity test.
Test method:Tetrazolium reduction method (mtt assay).
Cell strain:Human lung cancer cell lines A-549 and MCF-7 cell strainHJ2mm.Above-mentioned tumor cell line is purchased from China
Academy of sciences's Shanghai school of life and health sciences cell bank.
Experimental procedure is as follows:
(a) preparation of sample:For solvable sample, dissolved per 1mg with 40 μ L DMSO, take 2 μ L dilute with 1000 μ L culture mediums
It releases, makes a concentration of 100 μ g/mL, then concentration is extremely used with culture solution serial dilution.
(b) culture of cell
1. the preparation of culture medium:Containing 800,000 units of Penicillin, 1.0g strepto-s in per 1000mL DMEM culture mediums (Gibco)
Element, 10% inactivated fetal bovine serum.
2. the culture of cell:By tumor cell inoculation in culture medium, 37 DEG C are put, 5%CO2It is cultivated in incubator, 3~5d
Passage.
3. determination sample is to the inhibiting effect of growth of tumour cell
10th generation cell EDTA- pancreatin digestive juice is digested, and be diluted to 1 × 10 with culture medium6/ mL is added to 96 holes
In tissue culture plate, per 100 μ L of hole, 37 DEG C are put, 5%CO2It is cultivated in incubator.After inoculation for 24 hours, addition culture medium is diluted
100 μ g/mL, 10 μ g/mL and 1 μ g/mL samples, per 100 μ L of hole, each concentration adds 3 holes, puts 37 DEG C, 5%CO2It is trained in incubator
It supports, adds in the MTT of 5mg/mL after 72h in cell culture well, per 10 μ L of hole, put 37 DEG C of incubation 3h, DMSO is added in, per 150 μ of hole
L is vibrated with oscillator, and Shi Jia Za is completely dissolved, with microplate reader under 570nm wavelength colorimetric.To be free of sample under similarity condition,
The cell of medium culture containing similary concentration DMSO calculates IC of the sample to growth of tumour cell as control50。
The result of test is as shown in table 1, table 2:
The inhibiting effect that 1. compound of table (I) grows cancer cell line A-549
The inhibiting effect that 2. compound of table (I) grows cancer cell line MCF-7
(2) according to embodiment 11, chlorobenzoyl chloride is used into 4- iodobenzoyl chlorides, 3- methoxy benzoyl chlorides or cinnamoyl respectively
Chloro replaces, other operations have been respectively synthesized quinazoline compounds (a), (b) and (c), structure are as follows with embodiment 11:
According to the above method by quinazoline compounds (a) obtained, (b) and (c) has carried out Breast cancer lines
MCF-7 and human lung cancer cell lines A-549 biological activity test, the results showed that quinazoline compounds (a), (b) and (c) is to human milk
The equal unobvious of adenocarcinoma cell strain MCF-7 inhibitions, quinazoline compounds (b) and (c) inhibit human lung cancer cell lines A-549
The equal unobvious of effect, active anticancer can not show a candle to benzamido benzo [d] azepineBase quinazoline (I).Concrete outcome such as table
3rd, shown in 4:
The inhibiting effect that 3. compound (a) of table, (b) and (c) grow cancer cell line MCF-7
The inhibiting effect that 4. compound (b) of table and (c) grow cancer cell line A-549
(3) method of reference literature (Rao, G.-W.et al.ChemMedChem, 2013,8 (6), 928-933) is prepared into
To 4- chloro-quinazolines, further according to embodiment 1, the chloro- 6- nitro-quinazolines of 4- are replaced with 4- chloro-quinazolines, other operations are the same as implementation
Example 1, has synthesized quinazoline compounds (d), and structure is as follows:
Quinazoline compounds (d) obtained have been carried out MCF-7 cell strainHJ2mm biology according to the above method to live
Property test, test result shows that quinazoline compounds (d) can not show a candle to chemical combination to the active anticancer of MCF-7 cell strainHJ2mm
Object (I).Concrete outcome is as shown in table 5:
The inhibiting effect that 5. compound (d) of table grows cancer cell line MCF-7
Claims (10)
1. a kind of benzamido benzo [d] azepine shown in formula (I)Base quinazoline compounds:
2. a kind of benzamido benzo [d] azepine shown in formula as described in claim 1 (I)Base quinazoline compounds
Preparation method, it is characterised in that the method is:
(1) compound shown in formula (II) is mixed with compound shown in formula (III), in organic solvent A, in basic catalyst B's
Under effect, 25~120 DEG C are reacted, and after the reaction was complete, reaction solution is isolated and purified, and compound shown in formula (IV) is made;Institute
Organic solvent A is stated selected from one of following:Chloroform, toluene, methanol, ethyl alcohol, propyl alcohol, isopropanol, acetonitrile or N, N- dimethyl formyl
Amine;The basic catalyst B is selected from one of following:Pyridine, diethylamine, triethylamine, quinoline, N, N- dimethylanilines, 4- diformazans
Aminopyridine, 4- pyrollidinopyridines or sodium carbonate;
(2) formula (IV) compound represented obtained by step (1) is dissolved in organic solvent D, under reducing agent E effects, 25
~100 DEG C the reaction was complete, reaction solution filtering, and formula (V) compound represented is made in the concentrate drying after filtrate decompression concentration;
The organic solvent D is one of following:Chloroform, toluene, methanol, ethyl alcohol, propyl alcohol, isopropanol, acetonitrile or N, N- dimethyl formyl
Amine;The reducing agent E is one of following:Iron powder/concentrated hydrochloric acid, iron powder/acetic acid, palladium carbon/ammonium formate or palladium carbon/hydrazine hydrate;It is described
Iron powder/concentrated hydrochloric acid refers to that the mixing of iron powder and concentrated hydrochloric acid arbitrary proportion, iron powder/acetic acid refer to the mixed of iron powder and acetic acid arbitrary proportion
It closes, the palladium carbon/ammonium formate refers to the mixing of palladium carbon and ammonium formate arbitrary proportion, and the palladium carbon/hydrazine hydrate is palladium carbon and hydration
The mixture of hydrazine arbitrary proportion;
(3) compound shown in formula (V) is mixed with chlorobenzoyl chloride or benzoyl oxide, under basic catalyst F effects, in organic
In solvent G, -10~50 DEG C the reaction was complete, and reaction solution is post-treated, and formula (I) compound represented is made;The base catalysis
Agent F is one of following:Pyridine, diethylamine, triethylamine, quinoline, N, N- dimethylanilines, 4-dimethylaminopyridine, 4- pyrrolidinyls
Pyridine or sodium carbonate;The organic solvent G is one of following:Tetrahydrofuran, dichloromethane, chloroform, ethyl acetate, ether, second
Nitrile, toluene or benzene;
3. method as claimed in claim 2, it is characterised in that:Compound shown in formula (III) described in step (1) and formula (II)
The ratio between shown compound, amount for the substance that feeds intake of basic catalyst B are 1.0 ﹕, 0.8~1.2 ﹕ 1.0~8.0;The organic solvent A
Dosage 10~50mL/g is calculated as with the quality of compound shown in formula (III)..
4. method as claimed in claim 2, it is characterised in that:Reaction solution described in step (1) isolates and purifies in step (1)
Method is:After the reaction was complete, solvent is evaporated off in reaction solution, concentrate is taken to be dissolved with organic solvent C, obtains lysate, so
It adds in the column chromatography silica gel of 1.0~2.0 times of weight of concentrate in backward lysate, after mixing, solvent is evaporated off, it is dry, it obtains dense
Mixture is filled column, then using volume ratio as 1 by the mixture of contracting object and silica gel:0.1~10 petroleum ether is mixed with ethyl acetate
Solution is eluant, eluent, collects the efflux containing target components, is concentrated under reduced pressure, dry, obtains formula (IV) compound represented;It is described
Organic solvent C is one of following:Ethyl alcohol, chloroform, tetrahydrofuran or ethyl acetate.
5. method as claimed in claim 2, it is characterised in that:In step (2), when the reducing agent E is iron powder/concentrated hydrochloric acid
Or iron powder/acetic acid, formula (IV) compound represented are with iron powder, the mass ratio that feeds intake of concentrated hydrochloric acid or acetic acid in reducing agent E
1.0 ﹕, 1.0~3.0 ﹕ 0.2~1.0;When the reducing agent E be palladium carbon/ammonium formate or palladium carbon/hydrazine hydrate, shown in formula (IV)
The mass ratio that feeds intake of palladium carbon, ammonium formate or hydrazine hydrate in compound and reducing agent E is 1.0 ﹕, 0.1~0.5 ﹕ 1.0~3.0.
6. method as claimed in claim 2, it is characterised in that:Step (3) carries out as follows:In -10~10 DEG C of items
Under part, into the organic solvent G solution of compound shown in formula (V) and basic catalyst F or toward compound shown in formula (V) and
The organic solvent G solution of chlorobenzoyl chloride or benzoyl oxide is added dropwise in basic catalyst F, drop finishes, and -10~50 DEG C of reactions 3~12 are small
When, gained reaction solution is post-treated to obtain compound shown in formula (I);Total dosage of the organic solvent G is with formula (V) shownization
The quality for closing object is calculated as 11~100mL/g.
7. method as claimed in claim 2, it is characterised in that:Compound shown in formula (V) described in step (3) and benzene first
Acyl chlorides or benzoyl oxide, basic catalyst F the ratio between the amount for the substance that feeds intake be 1 ﹕, 1.0~8.0 ﹕ 1.0~3.0;It is described organic molten
The dosage of agent G is calculated as 11~100mL/g with the quality of compound shown in formula (V).
8. method as claimed in claim 2, it is characterised in that:The method of step (3) reaction solution post processing is:It will reaction
Liquid filters, and filtrate steaming removal solvent takes concentrate to be dissolved with organic solvent H, obtains lysate, is then added in into lysate
After mixing, solvent is evaporated off in the column chromatography silica gel of 1.0~2.0 times of weight of concentrate, dry, obtains the mixing of concentrate and silica gel
Mixture is filled column, then using volume ratio as 1 by object:0.1~10 petroleum ether is eluant, eluent with ethyl acetate mixture, is received
Collect the efflux containing target components, be concentrated under reduced pressure, it is dry, obtain formula (I) compound represented;The organic solvent H is following
One of:Ethyl alcohol, chloroform, tetrahydrofuran or ethyl acetate.
9. benzamido benzo [d] azepine shown in formula (I) as described in claim 1Base quinazoline compounds are being made
It is standby to prevent or treat the application in human breast carcinoma drug.
10. application as claimed in claim 9, it is characterised in that the drug is with inhibition MCF-7 cell strainHJ2mm
The drug of activity.
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Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN1061411A (en) * | 1990-11-06 | 1992-05-27 | 美国辉瑞有限公司 | Be used to strengthen the active quinazoline derivant of antineoplastic agent |
CN1141633A (en) * | 1994-02-23 | 1997-01-29 | 辉瑞大药厂 | 4-heterocyclyl-substituted Quinazoline derivatives, method for prepn. of same and the use as anti-cancer agent |
CN103275018A (en) * | 2013-04-26 | 2013-09-04 | 浙江工业大学 | 4-(3-chloro-4-substituted anilino)-6-substituted carbamonyl quinazoline compounds, and preparation method and applications thereof |
CN104926737A (en) * | 2015-05-13 | 2015-09-23 | 浙江工业大学 | 4-(3-substituted-anilino)-6-substituent quinazoline compound, preparation method therefor and application thereof |
-
2018
- 2018-01-24 CN CN201810069196.8A patent/CN108129461B/en active Active
Patent Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN1061411A (en) * | 1990-11-06 | 1992-05-27 | 美国辉瑞有限公司 | Be used to strengthen the active quinazoline derivant of antineoplastic agent |
CN1141633A (en) * | 1994-02-23 | 1997-01-29 | 辉瑞大药厂 | 4-heterocyclyl-substituted Quinazoline derivatives, method for prepn. of same and the use as anti-cancer agent |
CN103275018A (en) * | 2013-04-26 | 2013-09-04 | 浙江工业大学 | 4-(3-chloro-4-substituted anilino)-6-substituted carbamonyl quinazoline compounds, and preparation method and applications thereof |
CN104926737A (en) * | 2015-05-13 | 2015-09-23 | 浙江工业大学 | 4-(3-substituted-anilino)-6-substituent quinazoline compound, preparation method therefor and application thereof |
Non-Patent Citations (1)
Title |
---|
于艳红: "新型4-取代胺基喹唑啉类化合物的合成及其抗肿瘤活性研究", 《浙江工业大学硕士学位论文》 * |
Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN111973601A (en) * | 2019-05-21 | 2020-11-24 | 浙江工业大学 | Application of cinnamyl amino quinazoline compound as EGFR (epidermal growth factor receptor) inhibitor in preparation of medicines |
CN111973601B (en) * | 2019-05-21 | 2022-02-11 | 浙江工业大学 | Application of cinnamyl amino quinazoline compound as EGFR (epidermal growth factor receptor) inhibitor in preparation of medicines |
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